Funding is requested to replace a 14-year-old Rigaku X-ray diffraction system, including replacing the existing Rigaku (two-port) RU-H3R rotating anode X-ray generator with a Rigaku (single-port) MicroMax-003 sealed tube X-ray generator, replacing the two R-AxisIV imaging plate detectors with one Saturn 165+ CCD detector, and replacing the two existing X-stream cryo systems with one Oxford Cobra cryo system. The two existing Osmic mirror systems and R-AxisIVs will be traded in for credit towards this new X-ray facility. The requested instrument is essential to the specific aims of the NIH-funded research of the major users of this system, which includes studying the molecular mechanisms of enzymes involved in fatty acid metabolism, proteins involved in pre-mRNA 3'-end processing and RNA polymerase II transcription initiation and termination, Ca2+ and TRPC channels, epigenetic regulation by PWWP domain proteins, proteins involved in transmembrane transport and oxidative DNA damage repair, development of new methods for determining structures of proteins by solid state NMR, mechanism of inhibition of small molecules directed against proteins with important roles in human diseases, and structural genomics on eukaryotic, especially human, proteins and their prokaryotic homologs. PUBLIC HEALTH RELEVANCE: X-ray crystallography provides information at the atomic level about the functions of biological macromolecules. The requested instrument will be a crucial component of research on proteins of fundamental biological importance, as well as structure-based drug discovery against human diseases (obesity, diabetes, cancer and others).